1. fMRI Studies of Motivation a. MID and GLP1R. As part of an collaboration with Dr. Leggio, we carried out an analysis of fMRI data in ADPs who completed the MID task. SBEIs role was to explore the association of genetic variations of GLP1R in alcohol dependent participants brain activations (Suchankova et al., 2015). The hormone glucagon-like peptide-1 (GLP-1) is involved in reward processing. There was a significant difference in brain activation in the right globus pallidus when contrasting the genotypes for the rs6923761 SNP. ADPs carrying the non-risk allele displayed lower BOLD response in the right globus pallidus than those carrying the risk allele when receiving notification of outcome for high reward. This finding indicates that individuals with the risk allele may have a dysfunctional reward system. b. MID and Varenicline. SBEI has created a modified version of the MID task, which uses naturalistic rewards such as food and alcohol, in place of monetary reward. This task is referred to as reward incentive delay (RID). Dr. Ramchandani investigated the efficacy of varenicline, a nicotinic receptor partial agonist, in drinking reduction. SBEI participated as a collaborator for this study. As part of the study, participants underwent an fMRI session in which they played the RID task to investigate the effect of varenicline on the brain reward system activated by alcohol cues. Cues signaling alcohol reward activated the ventral striatum, in the placebo group, but not in the varenicline group (Vatsalya et al., 2015). Medication repurposing of varenicline could be targeted towards reward-drinking individuals seeking help for treatment of alcohol use disorder. c. Reward Incentive Delay with Shock Task. We are currently conducting a novel translational study to explore the neural correlates of aversion resistant alcohol addiction using a paradigm, which adds an aversive component to the RID task. Light drinkers and non-treatment seeking heavy drinkers are being enrolled in an fMRI study, where they are able to earn points for real alcohol and food rewards at the risk of receiving a small electric shock. This study is ongoing. d. RID Task for Ghrelin Study. A study, conducted in collaboration with Dr. Leggio, uses the RID task to investigate the role of ghrelin, a neuropeptide involved in regulating hunger and reward perception, in alcohol craving and use in a population of non-treatment seeking heavy drinkers. e. Dynamic MID Task for NORAA Study. A dynamic version of the MID task is being utilized in a collaboration with Dr. Hibbeln. In this study the effects of Omega-3 in adults with ADHD is being investigated, through the response of reward system circuitry. SBEI has assisted in the design of this study and oversees the imaging components. f. Effort Task. SBEI has also examined the role of alcohol dependence in effort-based valuation. We investigated this phenomenon in a population of treatment seeking alcohol dependent participants and healthy controls. Participants underwent an fMRI scan during which they played a task, which instructed participants to exert effort, in order to earn a monetary reward (Grodin et al., under review). There were three trial types, two where the level of effort was indicated to the subject (low and high), and one experimental condition where there was no indication of the required effort. Behaviorally, ADPs were less motivated during high effort trials and were less willing to exert higher levels of effort when the effort level was undisclosed. During low effort and unknown effort cue presentation, ADPs displayed an increased BOLD signal in clusters containing the dorsal and ventral striatum, regions implicated in effort and motivational processing. 2. fMRI Studies of Decision-Making a. Risk Task. While it has been established that alcohol dependence is associated with an increase in risky decision-making, there has been less focus on the role of past performance in neural activations occurring during and after decision-making. SBEI sought to bridge this gap utilizing a risk-taking fMRI paradigm that gave participants updated feedback on cumulative earnings throughout the task (Gilman et al., 2014). We analyzed the dynamic influence of trial-to-trail changes in net gain and loss, examining the activation during choice and feedback phases when modulated by cumulative earnings. ADPs exhibited heightened striatal activation, when cumulative earnings were included as a covariate, during risky decision-making, compared to healthy controls. b. Ultimatum Task. Recently, we have conducted a study utilizing a modified version of the Ultimatum Game, a paradigm where participants are given an offer as to how to divide $20.00. Participants were given the option to accept or reject each offer. Previous studies have demonstrated that the insula plays a key role in the processing of unfair offers. Our fMRI results indicate higher activation in the HCs in the insular cortex to unfair offers that were later rejected. HCs insula activation may have acted as a mediator between an emotional response versus the risk of rejecting such offers. c. Prediction Error Task. One of the remarkable properties of the human brain is its ability to adapt decision-making based on the outcome of previous decisions. Such optimization occurs when the prediction of receiving a reward is in conflict with the outcome, known as a prediction error. We have implemented a modified version of the prediction error task, where participants must select which of two cues they believe is associated with monetary reward. The two cues switch roles pseudo-randomly, with the winning cue becomes the losing cue, and vice-versa. Preliminary results indicate that alcohol dependent participants increase their activation of the caudate and insula when experiencing a prediction error, in comparison to healthy controls. 3. fMRI and Experimental Treatments We provided imaging support for three experimental treatment studies investigating naltrexone, pexacerfont (CRF receptor antagonist), and aprepitant (neurokinin-1 (NK1) receptor antagonist) as potential treatments for participants with alcohol use disorders. Naltrexone increased the activation in the ventral striatum, which indicates that naltrexone may be beneficial in alcohol dependent participants because of its ability to increase ventral striatal activity, thus reversing the reward deficiency syndrome present in those with alcoholism (Spagnolo et al., 2014). Pexacerfont did not affect the BOLD signal in the anxious treatment seeking population evaluated in this study. However, we did observe predictable activation in the amygdala during the presentation of fearful faces in the placebo group, validating our fMRI measures (Kwako et al. 2015). Aprepitant robustly activated the vmPFC during the presentation of aversive stimuli in a population of treatment seeking ADPs with comorbid PTSD, which indicates that NK1 antagonist therapy may be a useful treatment to enhance extinction-based cue-exposure therapies (Kwako et al. 2015). Repetitive Transcranial Magnetic Resonance (rTMS) Study The Risk Task is being used as an index of rTMS effect in a pilot study of cortical stimulation and the role of the insula in risky decision-making. Our preliminary analysis indicates that risk taking behavior was differentially affected by rTMS, resulting in an increased percentage of safe choices, which was sustained at the 1-hr time-point. These results show that 1Hz rTMS modulates insula activity in healthy controls, inducing behavioral effects similar to those described in patients with insula lesions. Given that insula damage leads to profound decreases in drug craving and relapse, rTMS may represent a non-invasive tool to affect craving driven by the insula in addiction.